Pyrazole-1-carboxamidines



United States Patent This invention relates to new carhoxamidinecompounds having valuable pharmacological properties. More particularlythis invention relates to new substituted carboxamidines and to themethods by which such compounds are prepared.

The new compounds of the present invention may be represented by theFormula I t RCNA where R is a to 6 membered nitrogen containingheterocycle and tetrahydroisoquinolino, R is selected from the groupconsisting of hydrogen, and

wherein R is an .alkyl radical and A is selected from the groupconsisting of hydrogen,

. (fi --R3 in which R is an alkyl group having not more than 7 carbonatoms, and -S(O) R in which R is aryl or alk'aryl; together with theiracid salts. In the foregoing structure, the heterocyclic R groupincludes pyrrolidino, morpholino, pyrazolino, pyrazolo and piperidino,all of which may be substituted with lower .alkyl, di-lower alkyl andtri-lower alkyl radicals.

A preferred group of compounds Within the class represented by Formula Iabove constitutes those represented by the following structural FormulaII:

i R-CNA H (II) wherein R represents a member of the group consisting ofpiperidino, morpholino, pyrrolidino and pyrazolo together with the loweralkyl and di-lower alkyl homologs of each of these andtetrahydroisoquinolino; R represents 46-011 or hydrogen; A is selectedfrom the group consisting of hydrogen,

in which R is an alkyl radical having not more than 7 carbon atoms andin which R is selected from the group consisting of aryl and alkaryl;together with their ph-aImacolo-gical'ly acceptable acid salts.

As has been suggested, the new compounds of the present inventionpossess valuable pharmacological properties. More specifically, the newcompounds of the present invention are useful as hypoglycemic agents.When used for the foregoing purposes, the new compounds are administeredin dosage amounts of from 10 to 100 UL/kg. either orally or parenterallyin liquid or solid dosage 'ice forms. When used with such carriers, thecompound will be present in the carrier in an amount of from 0.1 toabout percent by weight. Dosage forms include injectables, elixirs,capsules, lozenges and tablets together with appropriate liquid or solidvehicles, excipients or carriers according to conventionalpharmaceutical practice.

According to one method of preparation, the new compounds of the presentinvention are prepared by reacting a carboxamidine salt such as forexample 3,5-dimethylpyrazole-l-carboxamidine nitrate, with excess aceticanhydride and excess triethyla mine or trimelthylamine or an equivalenttertiary base having a higher ionization constant than that of thepyrazole base starting material, in an alcohol solution. The alcoholused is preferably a low molecular weight alcohol such as methanol,ethanol or the like. The reaction mixture is allowed to stand for aperiod of time such as from minutes to 24 hours at room temperature orlower. Temperatures higher than room temperature are not preferred. Thealcohol is then removed, as by distillation, and the oil productchssolved in water and extracted in low molecular weight, waterimmiscible, ether or ester solvent such as diethyl ether or ethylacetate. The ethereal or ester solution is dried, filtered andevaporated. The residue containing the desired compound, can then berecrystallized from other or if desired the salt can be prepared, suchas for example the hydrochloride, by passing HCl through the etherealsolution of the product. The resulting crystalline hydrochloride is thenrecovered by filtration.

The monoacetyl compounds of the present invention, other than thepyrazole derivatives, may \be prepared by first reacting a selectedcarboxa-midine salt with one equivalent of an anhydrous alcohol solutionof sodium. The sodium salt resulting is filtered off and the filtrateevaporated to dryness. The solid residue obtained is then suspended inexcess ethyl acetate and refluxed with stirring for a period of from 10to 30 hours. The reaction mixture is then filtered and the filtrateevaporated to dry ne'ss. The residue is washed, preferably with ether,and the ether insoluble portion dissolved in hot ethyl acetate fromwhich the desired monacetyl derivative is obtained on cooling.

In the foregoing methods of preparation, the selected carboxarnidinesalt, such as for example the 3,5-dimethylpyrazole-l-carboxamidinenitrate referred to above, is prepared according to the method ofTheile, Annalen der Chemie, 302, 275-311 (1898). In this method, 1 moleof aminoguanidine nitrate is added, over a period of 1 /2 hours to 1mole of 2,4-pentanedione in ethanol. After refluxing for 2 /2 hours, thenitrate salt is obtained on cooling to 0 C. To prepare other suitableheterocyclic carboxamidines, the salt of 3,5-dimethylpyrazolecarboxamidine is reacted with the free base, such as for examplepyrrolidine, piperidine or the like, in a low molecular Weight alcoholsolution for a period of from 1 to 3 hours. Suitable alcohols for thispurpose include methanol, ethanol and the like. An .amidine shift occursin which the pyrrolidine replaces the dimethyl pyrazole, yielding thedesired pyrrolidino carboxamidine salt. This product, in the form of thenitrate salt, may then be converted to the sulfate form if desired bytreating with sulfuric acid in ethanol. In a similar manner, the otherstarting compounds identified in the examples which follow are prepared.It has been found that nitrate and sulfate salts are most satisfactoryfor purposes of the present invention.

In preparing compounds of the present invention encompassed within thoseincluded in Formula I in which the di-acetyl structure is desired, thatis wherein R is the selected carboxamidine salt, such as for examplepiperidine-l-carboxamidine sulfate, is first reacted with one equivalentof an ethanolic solution of sodium. Sodium sulfate is filtered off andthe filtrate evaporated to dryness. The residue is dissolved in etherand acetic anhydride added. A precipitate of the acetate salt of theguanidine starting material is obtained by filtration. The desiredproduct is then recoverable as the salt, such as the hydrochloride, bypassing HCl gas into the filtrate and recovering the crystalline productwhich separates out on cooling.

Reference now to the specific examples which follow will provide abetter understanding of the new compounds of the present invention andthe manner in which the same are prepared:

Example I 50 gms. (0.25 mol) of 3,5-dimethylpyrazole-l-carboxamidinenitrate and 290 gms. (2.0 moles) of triethylamine are dissolved in 1liter of dry methanol, cooled in an ice bath, 108 gms. (1.5 moles) ofacetic anhydride is added in one portion and the reaction mixtureallowed to stand for two hours at room temperature. The methanol is thenremoved in vacuo and the oil dissolved in 800 ml. of water. Thissolution is extracted with three 100 ml. portions of ether. The etherextracts are dried over anhydrous sodium sulfate, filtered, andevaporated in vacuo. 100 ml. of benzene is added and re-evaporated. Theresidue is dissolved in 600 ml. of dry ether and hydrogen chloride addeduntil the solution indicates a pH of 2. The crystalline hydrochloride isfiltered, washed with ether, and dried in vacuo over P Yield ofN-acetyl-3,S-dimethylpyrazole-l-carboxamidine hydrochloride is 44.8 gms.or 69%, MP. 146147 C. corr.

Example II To 8.85 gms. (.05 mole) of pyrrolidine-l-carboxamidinenitrate, a solution of 1.15 gms. (.05 mole) of sodium in 100 ml. ofanhydrous ethanol is added and stirred for thirty minutes whileprotected with a sodalime tube. The suspension is filtered and thefiltrate evaporated in vacuo. The solid residue is suspended in 200 ml.of ethyl acetate and refluxed with stirring for 20 hours. The reactionmixture is filtered and the filtrate Following the method of Example II,N-acetyl-morpholine-l-carboxamidine is prepared by reactingmorpholine-4-carboxamidine nitrate with an alcoholic solution of sodiumfollowed by refluxing with ethyl acetate.

Example IV Following the method of Example II,N-acetylpiperidine-l-carboxamidine is prepared by reactingpiperidinel-carhoxamidine nitrate with an alcoholic solution of sodiumfollowed by refluxing with ethyl acetate.

Example V According to the method of Example I, pyr-azole-lcarboxamidinenitrate in the presence of triethylamine is reacted with aceticanhydride to produce N-acetylpyrazole-l-carboxamidine.

Example VI Following the method of Example II, N-acetyl-1,2,3,4-tetrahydroisoquinoline-l-carboxamidine is prepared by reacting1,2,3,4-tetrahydroisoquinoline 1 carboxamidine nitrate in an alcoholicsolution of sodium followed by refluxing with ethyl acetate.

Example VII at 7. The solid material is filtered, washed with water and.

crystallized from 200ml. of hot aqueous ethanol.N-p-tolylsulfonyl-3,S-dimethylpyrazole-l carboxamldine is obtained, M.P.140141 C. corr.

Example VIII Following the method of the previous example,N-phenylsulfonylpyrrolidine-l-carboxamidine is prepared by reactingpyrrolidine-l-carboxamidine nitrate with benzene sulfonyl chloride.

Example IX 15.0 gms. (.04 mole) of piperidine-I-carboxamidine sulfate isstirred in ml. of absolute ethanol containing 1.81 gms. (.08 mole) ofsodium for 1 hour. The sodium sulfate is filtered off and the filtrateevaporated to dryness in vacuo. The residue is dissolved in 200 ml. ofdry ether and 8.15 gms. (.08 mole) of acetic anhydride is added. Aprecipitate forms immediately and afterstirring :for 1 hour andfiltering 6 gms. (20%) of the acetate salt of the starting material isobtained. HCl gas is passed into the filtrate and a yellow oil separateswhich crystallizes on scratching andcooling to 0 C. Onerecrystallization from 30 ml. of ethanol and 200 ml. of dry ether give5.0 gms. or 60% yield of N,N'-diacetyl-piperidine-l-carboxamidinehydrochloride, M.P. 166-168 C. corr.

Example X Following the method of Example II,N-acetyl-2,6-dimethylmorpholine-4-carboxamidine is prepared by reacting2,6-dimethylmorpholine-4-carboxamidine sulfate with an alcoholicsolution of sodium followed by refluxing with ethyl acetate.

Example XI Following the method of Example m, pyrrolidine-lcarboxamidinesulfate is reacted with an ethanolic solution of sodium. Afterfiltration of sodium sulfate the filtrate is evaporated to dryness andthe residue dissolved in ether to which solution acetic anhydride isadded. A precipitate forms, the acetate salt of the starting material,which is removed by filtration. Passing HCl gas into the filtrate willprecipitate N,N'-diacetyl-pyrrolidine-l-carboxamidine hydrochloride.

Example XII overnight. 5.8 gms. (60%) of N-octanoyl-pyrrolidine-1-carboxamidine is obtained. After one recrystallization from pet-ether,4.4 gms. (46% yield) of pure material is obtained, M .P. 7071 C. corr.

Example XIII According to the method previously described, N-acetyl-2,4-dimethylpiperidine-l-carboxamidine is prepared by reacting2,4-dimethylpiperidine-1 carboxamidine nitrate with an ethanolicsolution of sodium followed by refluxing with ethyl acetate.

Example XIV N,N-diacetyl-Z,4-dimethylpyrrolidine-1-carboxamidine isprepared according to the method of Example IX by reacting2,4-dimethylpyrrolidine-1 carboxamidine sulfate with analcohol solutionof sodium :followed by refluxing with acetic anhydride.

Example XV Following the method of Example VII,2,6-diethylmorpholine-4-carboxamidine nitrate is reacted with p-toluenesulfonyl chloride to produceN-p-tolylsulfonyl-Z,6-diethylmorpholinet-carboxarnidine.

Example XVI N-acetyl-3,5-diethyl-2-pyrazoline-l-carboxamidine isprepared by reacting 3,5-diethyl-2-pyrazoline-l-carboxamidine nitratewith acetic anhydride according to the method described in Example 1.

Example XVII Following the method of Example XII,N-heptanoylpiperidine-l-carboxamidine is obtained by reactingpiperidine-l-carboxamidine nitrate With an ethanol solution of sodiumfollowed by heating the sodium containing carhoxamidine with methylheptanoate following removal of the alcohol.

Various modifications may be made in carrying out the present inventionwithout departing from the spirit and scope thereof. Insofar as thesemodifications are within the purview of the attached claims, they are tobe considered as part of this invention.

The invention claimed is:

1. A member of the group consisting of a compound of the formula:

References Cited by the Examiner UNITED STATES PATENTS 2,408,694 10/1946Simons et al 260561 2,926,172 2/1960 Boehme et a1. 260247.2 2,951,8439/1960 Haack et a1 260288 2,993,062 7/1961 Moyle et a1 260561 3,693,6326/1963 Mull 260288 OTHER REFERENCES Brewer, Organic Chemistry, 2nd ed.,page 211 (1948).

Scott, Jour. of Org. Chem, vol. 22, pages 1568- (1957).

Scott et al., Jour. Amer. Chem. Soc., vol. 74, pages 4562-66 (1952).

WALTER A. MODANCE, Primary Examiner.

NICHOLAS S. RIZZO, JOHN D. RANDOLPH,

Examiners.

DON M. KERR, NATALIE TROUSOF,

Assistant Examiners.

1. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA: